Controlled drug delivery systems deliver drug to the body so as to establish therapeutically effective blood levels of the active ingredient and once these blood levels are achieved they continue to maintain constant blood levels for long durations by delivering the drug to the body at the same rate as the body eliminates the drug. By avoiding peaks and troughs in blood levels associated with conventional dosage forms, controlled drug delivery systems lower the incidence of adverse effects or side effects. Very importantly controlled drug delivery systems reduce the frequency of dosing leading to convenience to the patient in terms of dosing and compliance to the specified dosage regimens.
It is generally known that the rate at which an oral controlled drug delivery system delivers the drug into the blood is not the same as the rate at which it releases the drug into a test aqueous fluid because the gastrointestinal fluid's pH, composition and agitation intensity change with the specific location of the drug delivery system in the gastrointestinal tract i.e. from the stomach to the colon, fasted versus fed state, type and amount of food ingested, and also vary from individual to individual. In addition, the drug may not be absorbed in the same manner and propensity we move from the stomach to the colon. Some drugs have an “absorption window” i.e. they are absorbed only from the upper parts of the gastrointestinal tract, whereas there are others whose absorption from the colon is not uniform or complete. Thus, the location of the controlled drug delivery system in the gastrointestinal tract as well as the rate at which the controlled drug delivery system moves from the stomach to the colon represent important factors that need to be considered in the design of an oral controlled drug delivery system. It is thus known to those skilled in the art that an oral controlled delivery should be designed not only with a control on the rate at which it releases the drug over the drug delivery time period (temporal control) but also a control on the location from which it is delivered (spatial control). The spatial control can be achieved by prolonging the period of retention of the system in the stomach. Gastric retention systems are also beneficial when the drug is effective locally in the stomach. Drugs absorbed in the upper part of the gastrointestinal tract may exhibit variability in absorption due to inter and intra-individual variability in gastric emptying and gastrointestinal motility. This variation in absorption may be addressed by administering a dosage form comprising the drug such that a small part of the drug is available as immediate release, and a large part is available as sustained or controlled release.
One of the approaches that has been used for achieving spatial control involves increasing the gastric retention of sustained or controlled drug delivery systems by using a composition containing highly swellable polymers in admixture with a gas-generating agent to form systems that are large in size as well as capable of floating on gastric fluids. It has now become well recognized by those particularly skilled in the art that systems containing swellable polymers will instantly float on gastric fluids because the gas generated and entrapped within the system decreases the density. Swelling to a large size is an important factor in gastric retention of the system. Solids having a size less than 5 to 7 mm show delayed gastric emptying in fed conditions but they can still be emptied from the stomach because their size is smaller than the pyloric sphincter. Even floating systems of size less than 5 to 7 mm can be emptied if the patient is in supine position. The mean resting pyloric diameter is approx. 13+7 mm and it has been reported that dosage forms with a size of approx. 12-18 mm diameter in their expanded state would generally be excluded from the passage of the pyloric sphincter. The system should also be capable of retaining this size in the gastric fluids for long periods under agitational conditions created by gastric motility. Such large intact systems cannot be emptied until the arrival of the interdigestive migrating motor complex at the beginning of the interdigestive phase. The combination of increase in size and floatation results in increased gastric retention of the system. The prior art resulting in this current state of the art is described below.
U.S. Pat. No. 4,101,650 ('650) assigned to Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai discloses a formulation in which granules containing sodium bicarbonate, lactose and polyvinylpyrrolidone are coated with a layer of hydroxypropyl methylcellulose. These are then further coated with a suspension containing the active ingredient pepstatin and hydroxypropyl methylcellulose to form floating minicapsules of a diameter in the range of 0.1 to 2 mm. The drawback of this system is that the minicapsules are much smaller in size than required for long durations of retention in the stomach.
U.S. Pat. No. 4,777,033 ('033) assigned to Teijin Limited, discloses an oral sustained release pharmaceutical preparation comprising a lower alkyl ether of cellulose, polyacrylic acid or its pharmaceutically acceptable salt, a drug, and an effective amount of effervescent foaming agent. Tablets made from the composition however still retained the above-cited major disadvantages associated with the '650 prior art in that the tablets of the '033 system did not remain intact when subjected to dissolution testing.
U.S. Pat. No. 4,844,905 assigned to Eisai Co. discloses granules comprising a drug containing core; a middle gas-generating layer comprising sodium carbonate and organic acid; and an outer coat of an expandable polymer film. Although intended for remaining in the stomach, the granules have the disadvantage of small size.
Japanese Patent No. 63014715 assigned to Zeria Shinyaku Kogyo KK discloses a slow releasing composition comprising (A) a high-viscosity water-soluble polymer, preferably cellulose ether or polyvinyl alcohol, (B) crosslinked insoluble polyvinyl pyrrolidone, and (C) a component to foam in contact with gastric juice, preferably carbonate, especially calcium carbonate or precipitated calcium carbonate. The system does not however contain a part of the drug in immediate release form and a part in controlled release form and does not provide a biphasic release pattern. Thus, even at the start of the dosage regimen when there is no drug available in the body, the system may begin with a relatively slow rate of release as compared to that from an immediate release composition. Another disadvantage is that whereas polymers that are highly swellable as well as rapidly swellable may be desirable for achieving gastric retention, we have found that several cellulose ethers do not conform to these requirements.
U.S. Pat. No. 5,651,985 assigned to Bayer AG, claims a pharmacologically active composition comprising a pharmacologically active compound dispersed in a homogenous mixture on the molecular level of polyvinylpyrrolidone and a methacrylic acid polymer having an acidic number between 100 and 1,200 mg of KOH/g of polymer solid substance, and optionally a gas-forming additive. The system does not however contain a part of the drug in immediate release form and a part in controlled release form and does not provide a biphasic release pattern. The rate of swelling of these systems is also slow so that they do not achieve the desired large size in a short period of 15 to 30 minutes. Moreover in order to achieve homogeneity of the two polymers on the molecular level a cumbersome and expensive process such as freeze-drying is required.
PCT publication No. WO 00/15198 assigned to Ranbaxy Laboratories relates to a pharmaceutical composition comprising a drug, a gas-generating component, a swelling agent, a viscolyzing agent, and optionally a gel-forming polymer. The gas generating agents used are carbonates or bicarbonates. The swelling agent is a superdisintegrant such as cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose and sodium starch glycolate. The viscolyzing agent is a carbohydrate gum that viscolyzes instantly. The system does not however contain a part of the drug in immediate release form and a part in controlled release form and does not provide a biphasic release pattern.
PCT publication No. WO 01/10419 assigned to Ranbaxy Laboratories relates to a pharmaceutical composition comprising a drug, a sugar, a diluent and a gas generating agent, and PCT publication No. WO 01/10405 also assigned to Ranbaxy Laboratories relates to a pharmaceutical composition comprising a drug, inert oil, a sugar, a diluent and a gas-generating agent. These systems however are not capable of swelling to a desirable large size suitable for gastric retention, as they do not contain any swellable substance.
PCT publication No. WO 00/23045 assigned to Sanofi-Synthelabo discloses a pharmaceutical composition containing two or three layers and contains an active principle in association with an excipient modifying its release and a system capable of generating carbon dioxide in a swelling polymer hydrophilic matrix. Examples are provided where the active principle is in one layer containing swellable polymers as the excipient modifying its release and the second layer contains swellable polymer in association with a carbonate. The composition is in the form of bilayer or trilayer tablets. The system does not however contain a part of the drug in immediate release form and a part in controlled release form and does not provide a biphasic release pattern.
PCT publication No. WO 01/10417 assigned to Galenix Development discloses and claims a pharmaceutical composition containing at least one phase comprising an active principle in association with one or many excipients and a second phase called non-active, consisting of at least one gas-generating system and at least one hydrophilic polymer or a porous mineral compound; and wherein the active phase comprises at least 80% active principle. The limitation of using not more than 20% of a release rate controlling excipient limits the flexibility that a formulator has for obtaining the desired rate of release while providing a higher level of assurance of reproducibility of the release profile from batch-to-batch. On the other hand when rate-controlling excipients are chosen judiciously such that they provide a highly reproducible release profile even when used in small amounts they may not be rapidly and highly swellable themselves. The system of WO 01/10417 uses the non-active phase to achieve floatation, which is achieved by a low density resulting from entrapment of carbon dioxide in the non-active phase matrix.